p63α mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome

Alexey Fomenkov, Yi Ping Huang, Ozlem Topaloglu, Anna Brechman, Motonobo Osada, Tanya Fomenkova, Eugene Yuriditsky, Barry Trink, David Sidransky, Edward Ratovitski

Research output: Contribution to journalArticlepeer-review

Abstract

p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile α-motif. By two-hybrid screen we identified several proteins that interact with the p63α carboxyl terminus and its sterile α-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63α. Moreover the physical association of p63α and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63α-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63α to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.

Original languageEnglish (US)
Pages (from-to)23906-23914
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number26
DOIs
StatePublished - Jul 27 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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